Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/56—One oxygen atom and one sulfur atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

• the present invention relates to certain novel pyrimidinone compounds, processes for their preparation, intermediates useful in their preparation, pharmaceutical compositions containing them and their use in therapy, in particular in the treatment of atherosclerosis.
• WO 95/00649 (SmithKline Beecham pic) describe the phospholipase A2 enzyme Lipoprotein Associated Phospholipase A2 (Lp-PLA2), the sequence, isolation and purification thereof, isolated nucleic acids encoding the enzyme, and recombinant host cells transformed with DNA encoding the enzyme. Suggested therapeutic uses for inhibitors of the enzyme included atherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial infarction, reperfusion injury and acute and chronic inflammation. A subsequent publication from the same group further describes this enzyme (Tew D et al, Arterioscler Thromb Vas Biol 1996: 16;591-9) wherein it is referred to as LDL-PLA2.
• LDL-PLA2 Lipoprotein Associated Phospholipase A2
• Lp-PLA2 is responsible for the conversion of phosphatidylcholine to lysophosphatidylcholine, during the conversion of low density lipoprotein (LDL) to its oxidised form.
• the enzyme is known to hydrolyse the sn-2 ester of the oxidised phosphatidylcholine to give lysophosphatidylcholine and an oxidatively modified fatty acid.
• Both products of Lp-PLA2 action are biologically active with lysophosphatidylcholine, a component of oxidised LDL, known to be a potent chemoattractant for circulating monocytes.
• lysophosphatidylcholine is thought play a significant role in atherosclerosis by being responsible for the accumulation of cells loaded with cholesterol ester in the arteries. Inhibition of the Lp-PLA2 enzyme would therefore be expected to stop the build up of these macrophage enriched lesions (by inhibition of the formation of lysophosphatidylcholine and oxidised free fatty acids) and so be useful in the treatment of atherosclerosis.
• Lp-PLA2 The increased lysophosphatidylcholine content of oxidatively modified LDL is also thought to be responsible for the endothelial dysfunction observed in patients with atherosclerosis. Inhibitors of Lp-PLA2 could therefore prove beneficial in the treatment of this phenomenon. An Lp-PLA2 inhibitor could also find utility in other disease states that exhibit endothelial dysfunction including diabetes, hypertension, angina pectoris and after ischaemia and reperfusion. In addition, Lp-PLA2 inhibitors may also have a general application in any disorder that involves activated monocytes, macrophages or lymphocytes, as all of these cell types express Lp-PLA 2 . Examples of such disorders include psoriasis.
• Lp-PLA2 inhibitors may also have a general application in any disorder that involves lipid peroxidation in conjunction with Lp-PLA2 activity to produce the two injurious products, lysophosphatidylcholine and oxidatively modified fatty acids.
• Such conditions include the aforementioned conditions atherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial infarction, reperfusion injury and acute and chronic inflammation. Further such conditions include various neuropsychiatric disorders such as schizophrenia (see Psychopharmacology Bulletin, 31, 159-165, 1995).
• Patent applications WO 96/12963, WO 96/13484, WO96/19451, WO 97/02242, WO97/217675, WO97/217676, WO 96/41098, and WO97/41099 disclose ter alia various series of 4-thionyl/sulfinyl/sulfonyl azetidinone compounds which are inhibitors of the enzyme Lp-PLA2- These are irreversible, acylating inhibitors (Tew et al, Biochemistry, 37, 10087, 1998).
• WO 99/24420 (SmithKline Beecham) describes a new class of compounds which are inhibitors of Lp-PLA2, namely a group of pyrimidone compounds.
• pyrimidone compounds which have a 5-(2-oxopyrimid-5- ylmethyl) substituent and which are potent inhibitors of Lp-PLA2
• the present invention provides a compound of the formula (I):
• R 1 is COOH or a salt thereof, COOR 10 , CONR 1 l R 12 , CN or CH 2 OH;
• R 2 is a mono- or bicyclic aromatic ring system containing up to 10 carbon atoms in the ring system, or a mono- or bicyclic heteroaromatic ring system including up to 4 heteroatoms selected from N, O and S; optionally substituted by 1, 2, 3 or 4 substituents selected from C j ⁇ alkyl, C ⁇ _ 4 aTkoxy, C ⁇ _ 4 alkylthio, aryl, aralkyl, hydroxy, oxo, halogen, CN, COOH or a salt thereof, COO-C,.
• R 3 is C ⁇ _ 2 o alkyl, C3.6 cycloalkyl, C 3 .6cycloalkylC ⁇ .5alkyl, or C1 _ ⁇ o alkoxyCi _ ⁇ o alkyl, each optionally substituted by 1 or 2 substituents selected from hydroxy, C ⁇ io alkoxy, COOH or a salt thereof, COOC1.15 alkyl, CONR 17 R 18 , NR 17 R 18 ' NR 17 COR 18 , NR ⁇ 9 0 r an aromatic or heteroaromatic ring system as defined for R 2 , or R3 is an aromatic or heteroaromatic ring system as hereinbefore defined for R 2 ;
• RIO is C ⁇ _ 4 alkyl or a pharmaceutically acceptable in vivo hydroly sable ester group
• R! 1 and R ⁇ 2 which may be the same or different is each selected from hydrogen, C 2 alkyl, CH2R 13 , CHR 14 CO2H or a salt thereof, or R 1 1 and R 12 together with the nitrogen to which they are attached form a 5- to 7 membered ring optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur, and optionally substituted by one or two substituents selected from hydroxy, oxo, C ⁇ _4alkyl, C ⁇ _4alkylCO, aryl, e.g. phenyl, or aralkyl, e.g benzyl, for instance morpholine or piperazine;
• R 13 is COOH or a salt thereof, COOR ⁇ , CONR 1 *R 12 , CN or CH 2 OH;
• Rl4 i s an amino acid side chain such as CH2OH from serine
• Rl5 and R ⁇ 6 are independently hydrogen or C 1.4 alkyl e.g. methyl or ethyl
• Rl and Rl8 are independently hydrogen, C1. ⁇ 5 alkyl, eg methyl or ethyl, C1 _I Q alkoxyCi .10 alkyl or arylCi _io alkyl, e.g. benzyl;
• Rl9 together with the nitrogen atom to which it is attached forms a 5- to 7 membered ring optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur, and optionally substituted by one or two substituents selected from hydroxy, oxo, C1.4 alkyl, aryl, e.g. phenyl, or aralkyl, e.g benzyl;
• W is SO 2 or a bond
• X is O or S
• R ⁇ include carboxy (COOH) and corresponding salts, esters (COORlO) and amides (CONRl 1R ⁇ 2 ) thereof, for instance a sodium salt, an ethyl ester or an amide comprising an N-alkyl substituent, for instance, methyl, 2-methoxyethyl, octyl, dodecyl, N-benzyl, N-naphthylmethyl or a disubstitued amide comprising a combination thereof, or an amide in which the N forms part of a heterocyclic ring, for instance a piperidine ring.
• Representative examples of the aromatic ring system represented by R 2 include phenyl and naphthyl.
• Representative examples of the heteroaromatic ring system which may be represented by R 2 include pyridyl, pyrimidinyl, pyrazolyl, furanyl, thienyl, thiazolyl, quinolyl, benzothiazolyl, pyridazolyl and pyrazinyl.
• Representative examples of R 2 include the phenyl group optionally substituted by 1 , 2 or 3 substituents selected from halogen (e.g. chlorine or fluorine), Cj_4 alkyl (e.g. methyl or ethyl) or Ci .4 alkoxy (e.g. methoxy), for instance 4-fluorophenyl.
• Examples of the aryl and aralkyl substituents in the R 2 group include respectively phenyl and benzyl.
• R 3 include C ⁇ _ 20 alkyl, for instance methyl and undecyl, and R 17 R 18 NHCOCH2 in which R ⁇ 7 and R 18 is each independently C ⁇ .
• ⁇ alkyl for instance R1 7 is methyl and Rl8 i s methyl, octyl, or dodecyl.
• W is a bond
• R W is N-(l-Dodecyl)-N-methylaminocarbonylmethyl.
• the group X is preferably S.
• Preferred compounds of formula (I) include those in which Y is a bond, i.e. A*, A 2 and A 3 each representing a bond.
• Other preferred examples of the groups A ⁇ and A 3 are straight chain alkylene groups.
• a ⁇ is preferably a bond.
• Other preferred examples of Y are (CH2)7 or CO(CH2)6-
• compositions for R ⁇ O include those which break down readily in the human body to leave the parent acid or its salt.
• R ® Representative examples of values of pharmaceutically acceptable in vivo hydrolysable ester groups for R ® include: -CH(Ra)O.CO.R b ; -CH(R a )O.CO.OR c ; -CH(Ra)CO.NR e R f -R d NReRf; -CH 2 ORg;
• R a is hydrogen, (Ci -6)alkyl, in particular methyl, (C3-7)cycloalkyl, or phenyl, each of which may be optionally substituted;
• Rb is (Ci -6)alkyl, (C ⁇ -g)alkoxy(C ⁇ -6)alkyl, phenyl, benzyl, (C3-7)cycloalkyl,
• R a and R D together form a 1 ,2-phenylene group optionally substituted by one or two methoxy groups;
• R c is (C ⁇ -6)alkyl, (C3-7)cycloalkyl, (C ⁇ -6)alkyl(C 3 -7)cycloalkyl;
• R" is (Ci -6)alkylene optionally substituted with a methyl or ethyl group; R e and Rf which may be the same or different is each (C ⁇ -g)alkyl; or ary C ⁇ -4) alkyl, optionally substituted with e.g. hydroxy;
• Rg is (C ⁇ -6)alkyl
• R n is hydrogen, (C ⁇ -6)alkyl or phenyl
• R 1 is hydrogen or phenyl optionally substituted by up to three groups selected from halogen, (Cj-g ⁇ alkyl, or (C ⁇ -6)alkoxy; and ⁇ l is oxygen or NH; for instance:
• acyloxyalkyl groups such as acetoxymethyl, isobutyryloxymethyl, pivaloyloxymethyl, benzoyloxymethyl, ⁇ -acetoxyethyl, ⁇ -pivaloyloxy ethyl,
• alkoxy/cycloalkoxycarbonyloxyalkyl groups such as ethoxycarbonyloxymethyl, t- butyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, 1- methylcyclohexyloxycarbonyloxymethyl and ⁇ -ethoxycarbonyloxyethyl;
• dialkylaminoalkyl especially di-loweralkylamino alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl;
• acetamido groups such as N,N-dimethylaminocarbonylmethyl, N,N-(2- hydroxyethyl)aminocarbonylmethyl
• lactone groups such as phthalidyl and dimethoxyphthalidyl
• Representative examples of pharmaceutically acceptable in vivo hydrolysable ester groups for R 10 include:
• alkyl and similar terms such as “alkoxy” include all straight chain and branched isomers.
• compounds of the present invention may include a carboxy group as a substituent.
• Such carboxy groups may be used to form salts, in particular pharmaceutically acceptable salts.
• Pharmaceutically acceptable salts include those described by Berge, Bighley, and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19.
• Preferred salts include alkali metal salts such as the sodium and potassium salts.
• Compounds of formula (I) are inhibitors of Lp-PLA2 and as such are expected to be of use in treating atherosclerosis and the other disease conditions noted elsewhere. Such compounds are found to act as inhibitors of Lp-PLA2 in in vitro assays .
• Particularly preferred compounds of formula (I) include:
• the compounds of the present invention are intended for use in pharmaceutical compositions, it will be understood that they are each provided in substantially pure form, for example at least 50% pure, more suitably at least 75% pure and preferably at least 95% pure (% are on a wt/wt basis). Impure preparations of the compounds of formula (I) may be used for preparing the more pure forms used in the pharmaceutical compositions.
• the purity of intermediate compounds of the present invention is less critical, it will be readily understood that the substantially pure form is preferred as for the compounds of formula (I).
• the compounds of the present invention are obtained in crystalline form.
• solvent of crystallisation may be present in the crystalline product.
• This invention includes within its scope such solvates.
• some of the compounds of this invention may be crystallised or recrystallised from solvents containing water. In such cases water of hydration may be formed.
• This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.
• different crystallisation conditions may lead to the formation of different polymorphic forms of crystalline products.
• This invention includes within its scope all polymorphic forms of the compounds of formula (I).
• Compounds of the present invention are inhibitors of the enzyme lipoprotein associated phospholipase A2 (Lp-PLA2) and as such are expected to be of use in therapy, in particular in the treatment of atherosclerosis.
• Lp-PLA2 lipoprotein associated phospholipase A2
• the present invention provides a compound of formula (I) for use in therapy.
• the compounds of formula (I) are inhibitors of lysophosphatidylcholine production by Lp-PLA2 and may therefore also have a general application in any disorder that involves endothelial dysfunction, for example atherosclerosis, diabetes, hypertension, angina pectoris and after ischaemia and reperfusion.
• compounds of formula (I) may have a general application in any disorder that involves lipid peroxidation in conjunction with enzyme activity, for example in addition to conditions such as atherosclerosis and diabetes, other conditions such as rheumatoid arthritis, stroke, inflammatory conditions of the brain such as Alzheimer's Disease, myocardial infarction, reperfusion injury, sepsis, and acute and chronic inflammation. Further such conditions include various neuropsychiatric disorders such as schizophrenia (see Psychopharmacology Bulletin, 31, 159-165, 1995).
• Further applications include any disorder that involves activated monocytes, macrophages or lymphocytes, as all of these cell types express Lp-PLA 2 .
• disorders include psoriasis.
• the present invention provides for a method of treating a disease state associated with activity of the enzyme Lp-PLA 2 which method involves treating a patient in need thereof with a therapeutically effective amount of an inhibitor of the enzyme.
• the disease state may be associated with the increased involvement of monocytes, macrophages or lymphocytes; with the formation of lysophosphatidylcholine and oxidised free fatty acids; with lipid peroxidation in conjunction with Lp PLA2 activity; or with endothelial dysfunction.
• Compounds of the present invention may also be of use in treating the above mentioned disease states in combination with anti-hyperlipidaemic or anti-atherosclerotic or anti- diabetic or anti-anginal or anti-inflammatory or anti-hypertension agents.
• examples of the above include cholesterol synthesis inhibitors such as statins, anti-oxidants such as probucol, insulin sensitisers, calcium channel antagonists, and anti-inflammatory drugs such as NSAIDs.
• the compounds of the present invention are usually administered in a standard pharmaceutical composition.
• the present invention therefore provides, in a further aspect, a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.
• Suitable pharmaceutical compositions include those which are adapted for oral or parenteral administration or as a suppository.
• Compounds of formula (I) which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
• a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
• a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
• a composition in the form of a capsule can be prepared using routine encapsulation procedures.
• pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
• Typical parenteral compositions consist of a solution or suspension of the compound of formula (I) in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
• a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
• the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
• a typical suppository formulation comprises a compound of formula (I) which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats.
• the composition is in unit dose form such as a tablet or capsule.
• Each dosage unit for oral administration contains preferably from 1 to 500 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the formula (I).
• the daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 1000 mg, preferably between 1 mg and 500 mg, or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 25 mg, of the compound of the formula (I), the compound being administered 1 to 4 times per day.
• the compounds will be administered for a period of continuous therapy, for example for a week or more.
• R 2 , R 3 , W, X and Y are as hereinbefore defined; with an alkylating agent of formula R!-CH 2 -L1 in which R ⁇ is as hereinbefore defined and L* is a leaving group such as chloride, bromide, iodide or mesylate, in the presence of a base such as potassium carbonate; and thereafter, and if necessary, intercon verting groups in R , for example COOR ⁇ to COOH by standard conditions (alkaline hydrolysis, hydrogenation of benzyl ester, etc), or COOH to CONRl 1R ⁇ 2 by amide coupling.
• a compound of formula (II) can conveniently by prepared by O-dealkylation of the corresponding compound of formula (III):
• R ⁇ is C 1 4 alkyl, arylmethyl or diarylmethyl and R 2 , R 3 , W, X and Y are as hereinbefore defined.
• Typical conditions include treatment with boron tribromide or B- bromocatecholborane in dichloromethane at temperatures between -20° and ambient; hydrogenolysis of benzyloxy groups; acid cleavage of O-tBu.
• a compound of formula (III) may be readily prepared in a series of steps from a compound of formula (IV):
• R 2 is hydrogen or C ⁇ _4 alkyl, for instance methyl or ethyl
• R 22 is hydrogen or methyl
• R 2 ⁇ is as hereinbefore defined; using procedures well known in the art for thiouracil formation, N-alkylation and thioetherification .
• a compound of formula (IV) in which R 2 * is hydrogen and R 22 is methyl may be treated with oxalyl chloride in a dry solvent such as dichloroethane, to form an intermediate acyl chloride, followed by treatment with potassium thiocyanate in the presence of a solvent such as acetonitrile, and then treatment with a compound of the formula (V):
• a compound of formula (IV) in which R ⁇ is Ci .4 alkyl, for instance methyl, and R 22 is methyl may be treated with thiourea, to form a thiouracil of the formula (VIII):
• Compounds of formula (IV) may be readily obtained from a convenient, readily available pyrimdine starting material such as a 2-alkoxy 5-bromopyrimidine, using processes well known in the art.
• This pyrimidine may be coupled with an acrylate ester such as ethyl or methyl acrylate, using a Heck reaction, and the intermediate then subjected to catalytic hydrogenation to give a propionic acid ester derivative.
• This in turn may be treated with methyl formate in the presence of a strong base such as potassium t-butoxide or sodium hydride, to give a compound of formula (IV) in which R 22 is hydrogen.
• a compound of formula (IV) in which R 22 is alkyl may be obtained from the corresponding ester by hydrolysis under basic conditions, for instance aqueous sodium hydroxide.
• the crude material was purified by flash chromatography (fine silica, methanol-ethyl acetate) to give 0.9 g of material that was dissolved in dry dimethylformamide (15ml) and heated with ethyl bromoacetate (0.17ml) and anhydrous potassium carbonate (0.43g) (oil bath 70°C) with stirring for 2h. The solvent was evaporated and the residue treated with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO 4 ), evaporated and purified by flash chromatography (fine silica, methanol-ethyl acetate) to give the title compound as an oil, yield 0.52 g.
• Example 16 The acid of Example 16 (4.9 lg) was added to a solution/suspension of sodium bicarbonate (0.64g) in water (60ml). The mixture was stirred at room temperature for 5 min and at 50°C for 5 min. After sonication for 8 min at room temperature, further water (100ml) was added and the undissolved material broken up. The mixture was heated and stirred for a further 5 min at 50°C and sonicated for a further 8 min at room temperature. Any remaining solid was filtered off and washed with water. The clear filtrate was freeze-dried for 16h to give the sodium salt.
• Enzyme activity was determined by measuring the rate of turnover of the artificial substrate (A) at 37 C in 50mM HEPES (N-2-hydroxyethylpiperazine-N -2- ethanesulphonic acid) buffer containing 150mM NaCl, pH 7.4.
• HEPES N-2-hydroxyethylpiperazine-N -2- ethanesulphonic acid
• Recombinant LpPLA2 was purified to homogeneity from baculovirus infected Sf9 cells, using a zinc chelating column, blue sepharose affinity chromatography and an anion exchange column. Following purification and ultrafiltration, the enzyme was stored at 6mg/ml at 4°C. Assay plates of compound or vehicle plus buffer were set up using automated robotics to a volume of 170 ⁇ l. The reaction was initiated by the addition of 20 ⁇ l of lOx substrate (A) to give a final substrate concentration of 20 ⁇ M and 10 ⁇ l of diluted enzyme to a final 0.2nM LpPLA2.
• the reaction was followed at 405 nm and 37 °C for 20 minutes using a plate reader with automatic mixing.
• the rate of reaction was measured as the rate of change of absorbance.

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